Chronic bacterial infections remain a significant cause of morbidity and mortality in human and animal populations. Current research efforts focus on generating effective preventative measures through vaccine development and on developing new antimicrobial agents to overcome rapidly increasing numbers of resistant microbes. Despite these efforts, the overall incidence of antibiotic resistance associated with chronic bacterial diseases continues to rise.
Intracellular pathogens, such as Mycobacterium, Salmonella, Chlamydia, Borrelia, Rickettsia, and Brucella, are particularly difficult to treat because they infect an intracellular niche inside of cells that protects them from being exposed to extracellular host defenses and high concentrations of antibiotics.
A specific example of a difficult to treat intracellular microbial pathogen is Brucella spp. Brucella are facultative intracellular pathogens of humans and domestic animals. Human brucellosis is strictly zoonotic and manifests as a chronic, debilitating disease from which there is no protective immunity. Brucellosis in humans is considered the most common zoonotic infection worldwide. Human brucellosis has emerged in new areas of the world, particularly in central Asia, while numbers of cases in endemic areas have not been reduced.
Despite the successful use of live-attenuated strains for vaccination in animals, no human vaccine is available for human brucellosis, and vaccine strains approved for use in animals are pathogenic to humans. These disease characteristics contribute to the bacterium being listed as a Category B Bioterrorism Agent. A key to Brucella pathogenesis is the organism's ability to survive and replicate within host monocytes and macrophages. Virulent Brucella prevents the fusion of phagosomes with lysosomes. The bacteria then replicate in a secondary intracellular compartment that is not acidic and that is removed from normal vesicle trafficking pathways.
Antibiotic resistance is not a hallmark of persistence within the host for intracellular pathogens compared to extracellular pathogens. A remarkably small number of bacteria have adapted to survive and replicate within monocytes and macrophages by modifying the partitioning of the subcellular compartments within the infected cell to avoid degradation and go on to replicate. The adaptation to the intracellular environment provides protection by sequestration from most immune defenses. Species of several genera have adapted in such a manner, including Mycobacterium, Yersinia, Francisella, Brucella, Burkholderia, Salmonella, Bordetella, and Erhlichia. During the chronic stage of Brucellosis, the bacteria persist and replicate in tissue resident macrophages. Reaching bactericidal concentrations in intracellular environments has proven very difficult using currently used methods. Standard antibiotic regimens for treatment of Brucellosis often require two to three antibiotics given simultaneously for a minimum of 6 weeks. These regimen are difficult to follow and are often ineffective, and patient compliance is a significant problem.
Accordingly, new antimicrobial formulations are needed, such as formulations that can target and/or deliver antimicrobial agents to the intracellular environment of cells infected with bacterial pathogens. Antimicrobial formulations that provide enhanced bactericidal activity are also eagerly sought. Compositions and methods that render antibiotics effective during the chronic stages of a disease are also needed in the art.